Expression of the Tim3-galectin-9 axis is altered in drug-induced maculopapular exanthema.

BACKGROUND: Drug-induced maculopapular exanthemas (MPEs) are mediated by Th1 CD4+ T cells. One of the mechanisms of control of Th1 cells in homeostasis is the interaction between the checkpoint inhibitor Tim3 and its physiological ligand galectin-9 (Gal9). Disorders affecting this axis may be responsible for various autoimmune and immunological diseases. The aim of this study was to determinate the influence of the Tim3-Gal9 axis on the development of MPE induced by drugs. METHODS: Frequencies of different cell subsets and the expression of Tim3 and Gal9 were measured in peripheral blood by flow cytometry and in skin biopsies by immunohistochemistry. Gal9 expression was assessed by RT-qPCR; its release was measured by multiplex assay. The effects of blocking or enhancing the Tim3-Gal9 axis on monocyte-derived dendritic cell (moDC) maturation and T-cell proliferation were determined by flow cytometry. RESULTS: The expression of Tim3 was significantly reduced in peripheral blood Th1 cells and in the skin of MPE patients vs controls. Gal9 expression and release were significantly reduced in patient peripheral blood and moDCs, respectively. The addition of exogenous Gal9 significantly reduced Tim3+ Th1 proliferation, although Treg proliferation increased. CONCLUSION: This study showed the involvement of the Tim3-Gal9 axis in MPE. The reduced expression of Tim3 in Th1 cells together with the impaired expression of Gal9 in PBMCs and DCs appears to have a role in the development of the disease. The potential of Gal9 to suppress Th1 and enhance Treg proliferation makes it a promising tool for treating these reactions.

Polymorphisms in CEP68 gene associated with risk of immediate selective reactions to non-steroidal anti-inflammatory drugs.

Non-steroidal anti-inflammatory drugs (NSAIDs) are the main triggers of drug hypersensitivity reactions. Such reactions can be pharmacologically or immunologically mediated, but in both cases individual susceptibility can be influenced by genetic factors. Polymorphisms in centrosomal protein of 68 kDa (CEP68) have been associated with pharmacologically mediated NSAIDs reactions. Here, we evaluated this gene in immunologically mediated single-NSAID-induced urticaria/angioedema or anaphylaxis (SNIUAA) by analyzing 52 single nucleotide polymorphisms in CEP68 in 176 patients and 363 NSAIDs-tolerant controls. Two intronic variants (rs2241160 and rs2241161) were significantly associated with an increased risk of SNIUAA, suggesting CEP68 to be a key player in both types of NSAIDs hypersensitivity. However, we found no overlap with genetic variants previously associated with pharmacologically mediated hypersensitivity, pointing to a complex role for this gene and its potential use in the development of biomarkers of clinical utility to diagnose patients at risk of these reactions and to differentiate entities.

Variants of CEP68 gene are associated with acute urticaria/angioedema induced by multiple non-steroidal anti-inflammatory drugs.

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most consumed drugs worldwide because of their efficacy and utility in the treatment of pain and inflammatory diseases. However, they are also responsible for an important number of adverse effects including hypersensitivity reactions. The most important group of these reactions is triggered by non-immunological, pharmacological mechanisms catalogued under the denomination of cross-intolerance (CRI), with acute urticaria/angioedema induced by multiple NSAIDs (MNSAID-UA) the most frequently associated clinical entity. A recent genome-wide association study identified the gene encoding the centrosomal protein of 68 KDa (CEP68) as the major locus associated with aspirin intolerance susceptibility in asthmatics. In this study, we aimed to assess the role of this locus in susceptibility to CRI to NSAIDs by examining 53 common gene variants in a total of 635 patients that were classified as MNSAID-UA (n = 399), airway exacerbations (n = 110) or blended pattern (n = 126), and 425 controls. We found in the MNSAID-UA group a number of variants (17) associated (lowest p-value = 1.13 × 10(-6)), including the non-synonymous Gly74Ser variant (rs7572857) previously associated with aspirin intolerance susceptibility in asthmatics. Although not being significant in the context of multiple testing, eight of these variants were also associated with exacerbated respiratory disease or blended reactions. Our results suggest that CEP68 gene variants may play an important role in MNSAID-UA susceptibility and, despite the different regulatory mechanisms involved depending on the specific affected organ, in the development of hypersensitivity reactions to NSAIDs.